DE2651084A1 - BASIC SUBSTITUTES O- (2-HYDROXYPROPYL) -ALDOXIME, METHOD FOR THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT - Google Patents

Description

Γ "

HOECHST AKTIENGESELLSCHAFT, 67.30 Frarkfurt / Main 80

Delivery address: Hoechst Aktiengesellschaft, Werk faw & ri V ^Ό ^ Postfach 12 91 01, 6200 Wiesbaden

Patent application

Basic substituted 0- (2-hydroxypropyl) aldoximes, method for their production and their blindness as medicinal products

1- (2-Hydroxyethyl) -2-methyl-5-nitroimidazole (metronidazole) is Even today it is the standard preparation for the treatment of protozoal diseases, especially trichomoniasis. In addition, 1-alkyl-5-nitro-2-imidazole aldoximes and their alkyl ethers have already been described as active substances against protozoa.

A large number of nitrofuran derivatives are also known to which are antibacterial and fungistatic. On the other hand, efficacy against protozoa is reported less frequently. So shows 5-nitro-2-furanaldoxime (nifuroxime) has a good trichomonacidal effect when applied locally, but it lacks "systemic activity" However. The term "systemic activity" means that the substance after oral or parenteral administration in different organ systems by different methods, e.g. by fluorescence measurements or colorimetric measurements, is detectable and effective there.

The invention relates to basic substituted 0- (2-hydroxypropyl) aldoximes of the general formula I (see formula sheet), in which either

X is a methine group and Y is an oxygen atom or X is a nitrogen atom and Y is the group NR, where R is a hydrogen atom, a methyl, ethyl or hydroxyethyl group,

1 2
R and R independently of one another are a hydrogen atom, an alkyl or hydroxyalkyl group, in each case up to 6, preferably up to 4, carbon atoms or an aryl group with up to 10, preferably

12th

6 represent carbon atoms or the groups R and R of the remainder, R

also to a 5- to -N

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7-membered saturated ring can be combined, which optionally contains at most one further nitrogen, oxygen or sulfur atom as a heteroatom and which optionally by alkyl or hydroxyalkyl with up to 6, preferably up to k carbon atoms or by an aryl group with up to is substituted by 10, preferably up to 6 carbon atoms,

and their physiologically compatible acid addition salts with such organic or inorganic acids]} ¹ dtf 6 "allow the production of non-toxic salts.

The new compounds show a good systemic effect against Protozoa such as trichomonads, amoebas and trypanosomes. In the foreground here is the mentioned, known 5-nitroimidazoles and -furaneη superior trichomonacid activity. The trypanocide effect is with the Kitrofuranaldoxinen more strongly expressed than with the corresponding ilitroimidazole compounds. The nitrofuran derivatives also leave a certain amount of Recognize antifungal and antibacterial effectiveness. About that In addition, the compounds of the formula I according to the invention are extremely effective in vitro activity against Trichomonas vaginalis and Entacioebr histolytica.

The invention also relates to a method for producing the Aldoximes according to the formula I with the indicator that there are compounds with the structural element (a) (see formula sheet) and compounds with the grouping {£} (see formula sheet) by pushing the bridge element (CJ ^ -, - - --- = N-0-CH -CH-CH -

* OH ^d
linked by one

a) Aldehydes of the formula II (see formula sheet) or their reactive ones Aldehyde derivatives with 0- (3-amino-2-hydroxypropyl) hydroxylamines der ForiBel III (see formula sheet) or their salts converts or

b) Aldoximes of the formula IV (see formula sheet)

/ 3

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b 1) rait 2,3-epoxypropyl compounds of the formula V Z-CH ^ -CH-CIIp

in the presence of acid-binding agents to form the 0- (2 _f 3-3poxypropyl) aldoximes of the formula VI (see formula sheet) and their oxirane ring with the amines of the formula VII . E aminolytically opens or

b 2) to basic substituted Epoxyi ^ ropylverbindungen of formula VIII (see formula sheet) added or

b 3) with the amino alcohols of the formula IX (see Forcelblatt) in the presence converts acid-binding agents,

1 2
where in the above formulas X, Y, Ii and λ have the meaning given above and Z denotes a halogen, preferably chlorine or red, or a reactive sulfonic acid group transferred into their physiologically compatible ga'ure addition salary.

As reactive derivatives of the aldehydes II are their semi- or Full acetiles, mercaptals, aminalo and acylcle nn. oops Alciair.:, others Oxime, iiydrazone, wemicarbazono, Tliioceniicarba ^ one, the Cyanh / rrine or the hydrogen sulfite addition compounds can be used as nutritive agents will.

/ ¹ Ic starting compounds of the formula III are, for example, O- (3-tert-butylamino-2-hydroxypropyl) -hydroxylamine, 0- (3-dieth / laraino-2-hydroxypror> yl) -hydroxylamine, 0- (3- ^) ibutylanino-2-hydroxypropyl) hydroxylamine, O- £ 3-di (2-hydroxyethyl) amino-2-hydroxypropyl] hydroxylamine, O-Jj5- (N-methyl-N-phenylamino) -2-hydroxypropyl_j-hydroxylamine , 0- r3- (i-pyrrolidyl) -2-hydroxypropyl] -hydroxylamine, 0- / 3- (1-piperidyl) -2-hydroxypropylj-hydroxyl = amine, 0- [] 3 - (^ - morpholinyl) -2 -hydroxypropylj -hydroxylamine, 0- (3-hexa = methyleniir.ino-2-hydroxypropyl) hydroxylamine, 0- j 3- (2, f; -dimethyl-1-pyrrolidyl) 2-hydroxypropyl] hydroxylamine, 0- [j5- (2,6-dimethyl-1-piperidyl) -2-hydroxy = propyl-hydroxylamine, 0-jj5- (2,2,6,6-tetramethyl-1-piperidyl) -2-hydroxy = propyl-hydroxylamine , 0- [ "3 - (^ - methyl-1-piperazinyl) -2-hydroxypropylj hydroxylamine, 0- 3 - (^ - <2-hydroxyethyl> -1-piperazinyl) -2-hydro ^x ypropyll -

Λ 809850/0004

hydroxylamine and O- jJ - ^ - phenyl-i-piperazinylJ ^ -hydroxypropylJ hydroxylamine in question.

Suitable starting materials corresponding to formula IV are, for example 1-methyl-, 1-ethyl-, 1- (2-hydroxyethyl) -5-nitro-2-imidazole aldoxime and 5-nitro-2-furanaldoxime.

Preferred compounds according to formula V are, for example, epichlorohydrin, Epibromohydrin and 2,3-epoxy; ropyl benzenesulfonate, p-toluenesulfonate or methanesulfonate.

As amines of the formula VII, inter alia, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert. Butylamine, also the various honopentyl and hexylamines, and the secondary amines corresponding to the above primary amines, such as dimethylanine and other dialkylamines with up to 6, preferably up to k, carbon atoms in the alkyl radical, diethanolamine,! N-methylaniline and also cyclic amines, such as pyrrolidine, piperidine, morpholine, hexamethyleneimine, 2,5-dimethylpyrrolidine, 2,6-dimethylpiperidine, 2,2,6,6-tetramethylpiperidine, Tliianorpholiii, · tetrahydro-1 ^ -thiaain-i , 1-dioxide and piperazine are used, with the aweit nitrogen atom of the piperazine ring in ^ -Gtellung except hydrogen z.3. can also carry a (C ₁ -C ^) - alkyl, hydroxy (C ₁ -C ^) - alkyl or phenyl group, as in ^ -Methylpiperazine, h- (2-IIydroxyäthyl) -piperazin, * f-Phenylpiperazin.

The reactions are conveniently carried out in a solubilizing or distributing agent carried out. In process variant a), equimolar amounts of the reactants are preferably used in an aqueous-alcoholic solution.

The alkylation of the oximes IV according to procedure b) can, for example in anhydrous alcohols, hydrocarbons, aprotic solvents or an excess of alkylating agents either in the presence of basic ones Agents such as alkali or alkaline earth hydroxides, carbonates, hydrides or

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alcoholates or using the separately prepared alkali or Alkaline earth oximate. The aminolysis of the epoxies VI is advantageous in inert solvents such as alcohols, hydrocarbons or aprotic solvents.

The alcohols include methanol, ethanol, propanol, isopropanol, butanol or isobutanol and, as hydrocarbons, hexane, cyclohexane, benzene, toluene or xylene. Suitable aprotic solvents are dimethylformamide, Dimethylacetamide, K-methylpyrrolidone, tetramethylurea, Hexamethylphosphoric trisamide and dimethyl sulfoxide. If it is appropriate is maintained, the reaction can be increased or decreased Carry out pressure if working under atmospheric pressure is also preferred. The reaction temperatures can depending on the procedure between 0 ° C and the boiling point of the solvent used at the selected pressure. In alcoholic media, Atraospheric pressure is preferably between 20 and 100 C, worked around 100 C in aprotic solvents. The! Response times are always enough depending on the process variant from a few minutes to a few hours. The products of the process are obtained as bases and are expediently converted into non-toxic salts. For example, hydrogen halide acids are used for this purpose, especially hydrochloric acid, sulfuric, phosphoric, tartaric, maleic, funaric and acetic acid.

The basic substituted 0- (2-hydroxypropyl) aldoximes of the formula I permit the treatment of protozoal diseases in humans and animals, as described in 2.B. caused by infections with Triehomonns vaginalis, Entamoeba histolytica and various Trypanosorzien strains. The new compounds can be used both orally and locally. Oral administration usually takes place in the form of tablets or capsules which contain about 10 to 750 mg of the active ingredient per daily dose with an addition of common diluents and / or extenders. But the administration of microcapsules without the addition of such diluents and extenders \ is possible. Jellies, creams, ointments and suppositories are suitable for local use.

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The new. Process products are characterized by a safe action that is superior to the known comparative products metronidazole, i-methyl-J-nitro-S-imidazole aldoxime and nifuroxime, especially compared to trichoraonads _t in vitro and in vivo, while being well tolerated.

Effects against Trichomonas fetus , T ^ f - *** .V f / κ * -

- "~ ^w ———— _f j

The effectiveness against Trichomonas fetus was tested on albino mice (NMHI) of both sexes from their own colony addiction. The body weight of the animals was between 10 and 12 g. The test substances were administered orally with the help of a pharynx either in an aqueous solution or, in the case of poorly water-soluble compounds, as a methyl cellulose suspension in two equal individual doses, the first two hours before and the second two hours after the intraperitoneal infection with 19 million pathogens. Animal suspended in 0.5: · 1 "KuI turned ium Merck I", from Merck AG, Darmstadt, Germany. The preparation groups comprised k or 5 animals per test substance and dosage. For infection control, a collective of 10 infected but untreated mice was included in each experiment. A further group of 5 animals that were neither infected nor treated served as a null control.

6 days after the infection, all test animals were sacrificed and the pathogen density i:, i peritoneal exudate of the animals treated with the Vc process products or comparative preparations was assessed by comparison with that of the untreated infection control group using the following criteria:

ineffective: pathogen density compared to infection control not significantly reduced. Rating number: 3 \ h

effective: a) indicated: pathogen density moderately reduced compared to infection control. Evaluation number: 2

b) unsatisfactory: pathogen density significantly reduced compared to infection control. Evaluation number: 1

c) good: no more I pathogens detectable. Valuation number:

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Tabel

¹ preparation of dose in mg / kg po pathogen density (T. fetus) of. ^ or 5 animals

2 X 25th 2 X 20th 2 X 15th 2 X 12.5 2 X 50 2 X 25th 2 X 12.5 2 X 50 2 X 25th 2 X 12.5 2 X 50 2 X 25th 2 X 12.5 2 X 50 2 X kO 2 X 30th 2 X 25th 2 X 50 2 X 25th 2 X 12.5 2 X 6.25 2 X 50 2 X 30th 2 X 25th 2 X 20th

0 0 0 0 0 0 0 0 0 0 O 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 3 0 0 0 0 0 0 0 0 2 2 2 3 0 O 0 0 0 0 0 0 + 2 2 if 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O 1 2 2 3 0 0 0 0 0 0 0 0 0 0 0 0 3 2 3 3

15 2 χ 50 0 0 0 0

2 χ 25 0 0 0 0

_2x 12, f ^09850/00 8 ⁴ O 0 Z

Dose in -y- 2651084 0 O 0 0 0 0 fetus) of 2 χ 50 0 0 0 2 0 1 Table (continued) 2 χ 25 Pathogen density (T.
if or 5 animals 0 0 2 -P- if if Preparation of
example 2 χ 12, mg / kg Ρ ο. 0 Pathogen density (T.
if or 5 animals 3
if if
if if
if 16 Dose in 0 0 if if. ₊ fetus) of 2 χ 50 0 0 if if if - 2 χ 25 5 if Comparator product 2 χ 12, mg / kg p.o. 2
if Metronidazole 2 χ 150
2 χ 100 if 2 χ 50 if 3 2 x 25 5 if 1-methyl-5-nitro-
2-imidazole aldoxime Nifuroxime

Infection control

if if if if

+ died before the end of the experiment

Also superior to metronidazole in vitro action against Trichomonas vaginalis and Entamoeba histolytica settled for the products of the process prove. For example, for the compound of Example 10, the concentration that still kills it completely the Trichomonas vaginalie pathogen guarantees 0.15 / VmI for that In contrast, the comparator preparation metronidazole 2.5 to 5.0 / - / ml. The corresponding The limit of inhibition against Entamoeba histolytica is e.g.

/ 9

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Compound of Example 7 at 1 »25 ^ / ml, while the comparative preparation is only effective up to 5 / All.

Examples

1) O- j_3- (4-morpholinyl) -2-hydroxypropylj -i-methyl-S-nitro ^ - imidazole aldoxime hydrochloride (formula X, see FormeIblutt) according to process variant a)

4.55 g (0.03 mol) of Z-Formj'l-i-methyl-n-nitroimidazole ground: .n \ C ml of ethanol dissolved warm. After adding 7.5 g (O ₁ OJ mol) of 0-; 3- (4-Morpholinyl) -2-hydroxypropyl] hydroxylamine dihydrochloride in 15 ml of water at about ko C is added dropwise with a solution of 3.2 g (0.03 mol) of soda in 15 ml of water, with constant stirring began. H then stirred for hours at room temperature, then distilling the ethanol off under reduced pressure, diluted with water and extracted with Cxim Essigester (ethyl ester). After drying over sodium sulfate and evaporation under reduced pressure , the extract leaves 9.6 g of crude base (100% of theory). To convert it into the hydrochloride, the base is dissolved in dry dough ester and 0.03 mol of ethanolic hydrochloric acid is added dropwise with stirring and good cooling. Further purification of the filtered product is not usually necessary, but can, if necessary, be carried out by recrystallization from an ethanol / diethyl ether mixture. Are thus obtained 8.4 g of the compound of formula X (89 ^; of theory), 3chmelspunkt 195-196 ⁰ C (with decomposition).

C ₁₂ Ii ₂₀ ClN ₅ O ₅ (MW = 3 ^ 9.8)

Analysis: Range C * H _t 2i £ H 5 _t 76 # Cl 10.1 ^ H 20.02 Si Gef. C ^ 1.0 ^ JH 5.81 # Cl 9.78 * $ N 20.01 #

The same compound is also obtained by aninolysis according to procedure b) of 0- (2,3-epoxypropyl) -1 -methyl ^ -nitro ^ -imidazole aldoxime with morpholine.

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2) O- ^ 3- (4-morpholinyl) -2-hydroxypropylJ -5-nitro-2-furansldoxis: - hydrq chloride (Formula X I, see Foraielblatt) r.zch Verfa TATIONS ν rirmts a)

7.06 g (0.05 hol) 2-formyl-soitrovuran Viet man hex krurateraperatur in 80 al ethanol, mixed with 12.6 g (0.05 hol) 0- [_3- ( ⁱ f-morpholine71) -2 -hydroxy = propylj -hydroxylamine dihydrochloride in 25 ml of water and then a solution of 5.3 g (0.05 Hol) soda in 25 ml v / water is added dropwise with stirring at low temperature. The mixture is stirred for 5 hours at room temperature, then the ethanol is distilled off under reduced pressure, diluted with water to about 120 ml and the Oxira is extracted with ethyl acetate. After drying over sodium sulphate and zinc inoculum under reduced pressure, the extract yields 15 g of Eohbaee (100 £> of theory), which after being taken up in dry ethyl acetate by dropwise addition of approx. 0.05 mol of ethanolic hydrochloric acid with stirring and ice cooling in the crystalline Let the hydrochloride convert. If necessary, it can be recrystallized from ethanol / diethyl ether. This gives 15.5 S of the compound of the formula XI (92.2 # of theory), melting point 182-183 ° C. (with decomposition).

C ₁₂ H ₁₈ ClN ₃ O ₆ (MW = 335.7)

Analysis: Ber. C * f 2.93 # H 5 ^ 0% Cl 10.56 # N 12.52? I found. C ^ 2.7% ^ H 5, ^ 9 # Cl 10.51-- 'N 12.6o2

The same compound can also be prepared according to procedure b) by reacting 0- (2 _f 3-poxypropyl) -5-nitro-2-furanaldoxime with morpholine.

3) 0- (3-Diethylamino-2-hydroxypropyl) -1-methyl-5-nitro-2-imidasole = aldoxim-hydrochlorü (formula XIII, see formula sheet) according to

driven variant b)

1st stage: 0- (2,3-epoxypropyl) -1-methyl-5 " ⁿ J- ^ ^r o ~ 2-imidazole aldoxime (Formula XII, see formula sheet)

To a solution of 2.3 g (0.1 gram atom) of sodium in 300 ml of dry ethanol 17.0 g (0.1 mol) of i-methyl ^ -nitro-Z-imidazole aldoxime are added with stirring.

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A clear solution is obtained, which can be removed from the solvent in vacuo freed, whereby the sodium oxinate is obtained in solid form. The dry salt is suspended in 120 ml (1.5 mol) of idpichlorohydrin and refluxed heated. The implementation, which can be followed by thin-layer chromatography leaves, is finished after about 1 hour. It is diluted with chloroform, the precipitated sodium chloride is filtered off and the filtrate is evaporated in vacuo. 19.5 g (86.3> j) of crude product are obtained, from which approx. 250 ml boiling hot petroleum ether 1 ^, 7 g analytically pure, oily aldoxime der Let formula XII (65 / - 'of theory) be extracted.

° 8 ^Π 10 ^Ν ίΛ ^{(KG = 226) 2)}

Analysis: Ber. C 42 _f 48 # II k, k $% N 24.76 * 5
Ge f. C 42.15 # H Ί _t 28 # N 24, 7 h $

..J ^ i-El Acino lysis des Ep oxy ds with D
2.26 e (0.01 hol) of compound XII and 0.73 g (0.01 hol) diethylamine are heated under stirring and reflux in 20 nil n-propanol for k hours of icing. The solvent is then distilled off under reduced pressure and the residue is treated with ethanolic hydrochloric acid (0.01 mol). Upon careful addition of a little diethyl ether at the boiling point, 1.3 g of p- (3-diethylamino-2-hydroxypropyl) -1-methyl-5 "nitro-2-imidazole aldoxime hydrochloride (38.7% Theory) from a melting point of 210 ^° C.

C ₁₂ II ₂₂ ClH ₅ C ₁₊ (KG = 33 ?, 8)

Analysis: Ber. C ^ 2.92iö H 6. _t 6Ojä5 Cl 10.56 '"N 20.86 £ Gef. C ^ 2.69?" II 6.57 /; Cl 10.57? Ί N 20.7W

The same compound is obtained by reacting equimolar amounts 2-formyl-1-methyl-5-nitroimidazole and 0- (3-diethyle.raino-2-hydroxypropyl) -hydroxylanine dihydrochloride according to process method a) with a yield of 7850.

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The following connections can be made analogously both by process variant a) as well as b) produce:

* O 0- j3- (i-piperidyl) -2-hydroxy ^ r) ropylj -1-raethyl-5-nitro-2-iraidazole = aldo; cim hydrochloride; Melting point 170 ° C

5) 0- (3-tert-butylamino-2-hydro: cypropyl) -1-methyl-5 ^> -nitro-2-imida3ol = aldoxime hydrochloride; Melting point 218-220 ° C

6) O- (3-tert-butylamino-2-hydroxypropyl) -5-nitro-2-furanaldoxime-hydro = chloride; Melting point 178-179 ° C

7) 0- (3-Ethylamino-2-hydroxypropyl) -1-methyl-5-nitro-2-irriida: -; olaldoxine hydrochloride; Melting point 103 ° C

8) 0- (3-diethanolamino-2-hydroxypropyl) -1-methyl-5'-nitro-2-inidasole · aldoxime hydrochloride; Melting point 1 ^ 5 -1 ⁴ T- (J ⁰ C

9) 0- (3-diethanolaniino-2-hydroxypropyl) -5-nitro-2-furanaldoxiK-hydro = chloride; Melting point 155-156 ° C

10) 0- '■ 3- (N-methyl-N-phenylamino) -2-hydroxypropyl] -1-methyl-J-nitro-2-imidasolaldoxin> hydrochloride; Melting point 17-172 ° C

11) 0- \ j> - (N-methyl-N-phenylamino) -2-hydroxypropyl-5-nitro-2-furanaldoxime hydrochloride; Melting point 152 - 15 ^ ° C (with decomposition)

12) 0- f3- (i-Pyrroä [idyl) -2-hydroxypropy: n -1-methyl-5-nitro-2-imidazole = aldoxime hydrochloride; Melting point 190-191 ° C

13) 0- (3-Hexamethyleneimino-2-hydroxypropyl) -1-methyl-5-nitro-2-imidazole =

aldoxime hydrochloride; Melting point 170 ° C

0- (3-hexamethyleneimino-2-hydroxypropyl) -5-nitro-2-furanaldoxime hydrochloride; Melting point 15 * f - 156 ⁰ C

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- yr -

'/ b ö Ί υ ö

0 ~ | J5- (2,5-dimethyl-1-pyrrolidyl) -2-hydroxypropyl] -i-methyl-5-nitro-2-imidazole aldoxime hydrochloride; Melting point 200-202 ° C

16) 0- ι 3- (2,6-dimethyl-1-piperidyl) -2-hydroxyüropylj -1-methyl-5-nitro 2-imidasolaldoxime hydrochloride; Melting point 220 ° C

17) 0- [3- (2,6-dimethyl-1-piperidyl) -2-hydroxypropyl] -5-nitro-2-furanaldoxira hydrochloride; Melting point 130-181 ° C

18) 0- j "3- (2,2,6,5-tetramethyl-1-piperidyl) -2-hydroxypropyl -1-methyl-

^ - _o -r ^

J-nitro ^ -imidazole aldoxime hydrochloride; Snip point 186 C

19) 0- j 3- ( ⁱ ^ -Mc! Thyl-1-pipere.zinyl) -2-ilydro: cyprop;> rl] -i-methyl-pnitro-2-J

setting)

nitro-2-imidazole aldoxime dihydroclilorivi; Shrimp point 230 C (under decomposition

i -1

20) 0- j 3 - (^ - ß-Hydroxyäthjl-1-piperasinjrl) -2-liydroxypropylJ -1-methyl-5-nitro-2-imidazole aldoxime dihydrochloride: Melting point 190 ° C

21) 0-; 3 - ('+ - β-Hydroxyethyl-1-piperazinyl) -2-hydroxypropyl] -5-nitro-2-furanaldoxime dihydrochloride; Melting point 207 - 210 ⁰ G (with decomposition)

22) 0- J 3 - (^ - phenyl-1-piperazinyl) -2-hydroxypropylj -i-methyl-5-nitro-2-imidazole aldoxine monohydrochloride; Melting point I83 G (with decomposition)

23) 0- (3-Diethylamino-2-hydroxypropyl) -5-nitro-2-furanaldoxime-hydro = Chloride? Melting point 150-151 ° C

The synthesis of the basic substituted 0- (2-hydroxypropyl) -hydroxylamines used as starting materials is described in the patent (patent application P ^ Tft. T). The other starting compounds are known from the literature »

*) from the same registration day

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Fornielblatt

χ:

CII = HC-CII ₀ -CIi-CII ...- !! ':

OH (I)

(A)

CII =

(B)

(II)

CII = O

H ₂ K - 0 - CII ₂ - CII - CII ₂ - IK '- Oil

(III)

CH = N-OH

(IV)

^V CH = K - O - CII ₂ - CiI -

CII (VI)

809850/0004 copy

-. CII

- CIi - fj / (VIII)

2651Ό84

- CII - CH, -

Oil

(IX)

■ c: i.

WO-CIT -CII-CII ₀ -N

I Oil

^ c: i = i: -G-cj: _o -c: i-cif -ι;

. ² I 2,

. iici

CH = Ii-C-CII ₀ -CIi-CII.

(XII) '

/ ° 2 ^η 5

c: (X ₁₁₁ )

BAD ORiGiNAL COPY

Claims (1)

wherein either ° 2 ^{N V} _Y / ^^ CH = NO-CH ₂ -CII-CH ₂ -Nv. (I) χ is a kethine group and Y is an oxygen atom or X is a nitrogen atom and Y is the group NR, v: whether R is a hydrogen, methyl, ethyl or hydroxyethyl group, '' · 12th R and R independently of one another are a hydrogen atom, an alkyl or hydroxyalkyl group each having up to 6, preferably up to k, carbon atoms. or an aryl group with up to 10, preferably up to 6 carbon atoms 12 1 represent or the groups R and R of the radical / R also to one 5- to 7-membered saturated ring can be combined, which optionally contains at most one nitrogen, oxygen or sulfur atom as a hetero atom and which is optionally replaced by alkyl or! Hydroxyalkyl has in each case up to 6, preferably up to k, carbon atoms or through an aryl group with up to 10, preferably up to 6, carbon atoms. Atoms is substituted, and their physiologically acceptable acid addition salts with such organic or inorganic acids, dia producing non-toxic SaIse egg'lauben. / 2 809850/0004 ORIGINAL! MSPECTED [submitted later I. ?.) Vot'bindim _t ; tui according to Aunpr-uch 1, d - "'. L'. ¹ Vv-H f ^ koi'Ji / .i: ii-hnet, Λ-λ'.ϊ rlei · ge: : 'db ι.i ;; ': .-. ■ \ / ic l; cro <* ycli.; Icho, .i> egobört "jn. £ '." Ri.ln imbGl-U.uJ.3rl «ivt? Nt, K an« ciiiam Pyrrolidine, piperidine, morpholine, lIexaiaath; / lGniinin-, Thxarnorplinliii-, Tctrahyilro · -1, ^ thiazine-1,1-clioxyd- ~ or Pipevnviinreot consists. 3) Compounds according to claim 1 or 2, characterized in that the Heat 'H represents a flperasin residue, the «wide ßfcick- stoffcitom in the 'f-position optionally with alkyl, hydroxyalkyl or aryl is substituted. h) Compounds according to claim 1 or 2, characterized in that the radical M is a 2,5-dialkylpyrrolidine or a 2,6-dialkyl or -β / 2.2 ₁ 6,6 -'J? Etraalkylpiperidini ^> est represents. 5) compounds according to claim 2, characterized in that they 0- Z ~ 3- (^ -HorphinyT) -2-hydroxypropyl_7 -1-methyl-5-iiitro-2-imidazolaldoxii: hydrochloride or 0- (3-hexamethyleneimino.-2-hydroxypropyl) -1-methyl-5-nitro-2-iinidazülaldoxime hydrochloride are. 6) compounds according to claim * f, characterized in that they 0- / 3- (2,5-diraethyl-1-pyrrolidyl) -2-hydroxypropyl-y -1-raethyl-5 ~ uitro-2- · iraidaaolaldoxime hydrochloride or 0- ^ ~ 3- (2,6-dimethyl-1-piperidyl) -? .- hydroxypropylJ7 -i-raethyl ^ -nitro-S-imidazolaldoxirn hydrochloride oind. 7) Process for the preparation of compounds of the formula I according to claims 1 to 6, characterized in that compounds with the structural element (A) JTl (A) and compounds with the grouping (B) -H ^ (B) with the insertion of the bridge member (C) ^ R ² SH-O-CH ₂ -CH-CH- (C) "° H 809850/0004 / 3 BAD ORIGINAL COPY 5Y. ⁵ ^.! '''--' ■■ · "'···'>'- - J NACneeRElCHT linked with each other by ... "' a) Aldehydes der! 'orraol 9 RR 10ft U or their reactive aldehyde derivatives with C- (3-Amino-i? ~ hydroxypropyl) · hydroxylarainftn '3 er formula ^ _f . ·. · _-..... -. ₍ - H ₂ N - O - CH ₂ - CH- CH ₀ - H <f (HI) OIL odor converts their salts or
b) Old oxisie abv > 7ormel X ₁ CiI - = N - OH b 1) Kit 2, jj-ifyoxypropylverbindungen dor formula ■■. ·; ■■ * · - ■■ ■ "■ Z-Ci). -ςτΓ-cK '^;'" (v) · ■ ^: ■ • «.j .. ·: · ■! \) · -I'i '■ ■■ ·" in original givurt F. Kurobindendei · .Means? .u 0- (2 _J 5-epoxypropyl) -aldoximes of the formula CFi -; N ~ 0 - · CH., - CJ !. V- pil., "- (Vl) - Λ 809850/0004 / k j SUBMITTED implements and their Cb: innnring with Awinen of the formula 2651084 "1 HIK _n (VlT) aminolytically opens or b 2) to basic substituted Kpoxypropyl "compounds of the formula CH ₀ - CH - CH, - N ^ (VIII) O ^R added or b 3) with aim amino alcohols of the formula Z - CH ₀ - CH - CII - K _x (IX) OH
reacts in the presence of acid-binding agents, 1 2 where in the above formulas Z, Y, E and E specified in claim 1 Have meaning and Z is a halogen atom or a reactive sulfonic acid ester grouping means, and that the basic reaction products are also converted into their physiologically compatible »acid addition gals. 8) The method of claim 7i characterized in _t that one works in the presence of a solvent, wherein according to the procedure a) in aqueous alcoholic solution, and after operation) b in an aprotic solvent, an anhydrous alcohol "a hydrocarbon or vem / ended alkylating agent itself reacted will. 9) Medicines consisting of or containing a compound nt-ch one or more of claims 1 to 6 or a connection prepared according to the method according to claims 7 or 8. 10) Medicament according to claim 9 for fighting protozoa. Dr. LC '/ BU _{A ft Λ} , ίο. Μ, WS 80 98 BO / 0004